Monday, 24.02.2020

Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era.

New Clinical Methodologies in Develooment 1


The CODE System*

(Bulletin 77)


          There are two diagnostic instruments in development to provide pharmacologically more homogenous populations for research than the diagnostic categories of consensus-based classifications: the Composite Diagnostic Evaluation (CODE) System and Nosologic Homotyping. The CODE System is a methodology for the identification of the treatment responsive form of illness (population) if covered up by consensus-based or other broadly defined diagnoses. An important impetus for the development of the CODE-System was the finding of Frank Fish that the traditional diagnostic concept of schizophrenia covered up the powerful effectiveness of phenothiazine neuroleptics in a subpopulation of schizophrenia (Fish 1964). With the employment of Karl Leonhard’s classification of “endogenous psychoses,” he revealed that three of four patients with unsystematic schizophrenia, one of the two classes of disease subsumed under the diagnosis of schizophrenia, responded favorably to neuroleptic phenothiazines, whereas only about one of four patients with systematic schizophrenia showed a similar favorable response. Response rate in affect-laden paraphrenia, one of the three forms of unsystematic schizophrenia, was about 85%, whereas in the different forms of systematic schizophrenia response rates were below 25% (Ban 2007; Fish 1964; Leonhard 1957)

          The CODE System consists of a set of diagnostic instruments (“CODES”) that can provide for poly-diagnostic evaluation in distinct categories of mental illness by the employment of an integrated criteria list and standardized data collection. Each CODE consists of a vocabulary, or set of variables (“codes”), that include all the elementary units (variables) of the diagnoses in the component classifications; a structured interview that provides algorithms for the determination of the presence or absence of each variable; and diagnostic decision trees that provide diagnoses in all the component diagnostic systems (Ban 1991). In addition, each CODE includes a rating scale, based on a subset of variables from the vocabulary, for the determination of the severity of the clinical state across diagnoses. A unique characteristic of the CODE System is that it provides readily accessible information relevant to the diagnostic process from the lowest to the highest level of decision-making. The first set of provisional CODEs included poly- diagnostic algorithms for anxiety disorders (CODE-AD), depressive disorders (CODE-DD), hyperthymic disorders (CODE-HD) and schizophrenic disorders (CODE-SD) (Ban 2001; Gaszner and Ban 1998).




          The prototype of the CODE System is CODE-DD, the CODE for unipolar depressive disorders (Ban 1989). One of the contributing factors to its development was the recognition that the diagnosis of “vital depression” was covered up in consensus-based classifications, such as the DSM-III of the American Psychiatric Association (1980). Kurt Schneider’s “vital depression,” characterized by “corporization,” “disturbance of vital balance” and the “feeling of loss of vitality” is the form of depression that provided Roland Kuhn the necessary diagnostic end-point to recognize the antidepressant effect of imipramine (Kuhn 1957; Schneider 1920, 1950, 1958). In currently used consensus-based classifications the diagnosis of “vital depression” is covered up to the extent that even in a severely ill patient who displays all the possible symptoms and signs considered for the American Psychiatric Association DSM-III, DSM-III-R and DSM-IVTM diagnoses of “major depression” and the World Health Organization ICD-10 diagnosis of “depressive episode,” one still would not know whether the patient qualifies for “vital depression” (American Psychiatric Association 1980, 1987, 1994; World Health Organization 1992).

          CODE-DD consists of a 90-item vocabulary, a structured interview, a 40-item severity subscale and 25 diagnostic decision trees. Of the diagnostic systems included in CODE-DD three are based on the conceptual development of the classifications of depressive disorders in Europe (Kraepelin 1896, 1921; Leonhard 1957; Schneider1958); three on the conceptual development of classifications in North America (Feighner, Robins, Guze et al. 1972; Robins and Guze 1972; Spitzer, Endicott and Robins 1978); two are consensus-based classifications, one based primarily on the consensus of experts in the USA (American Psychiatric Association 1987) and one on the consensus of experts in Europe (World Health Organization 1988); 10 are empirically derived classifications, the result of factor or cluster analyses of psychiatric rating scales (Foulds 1973, 1976; Hamilton and White 1959; Lewis 1934; Kiloh and Garside 1963; Mendels and Cochrane1968; Overall, Hollister, Johnson and Pennington 1966; Paykel 1971; Pilowsky, Levine and Boulton 1969; Raskin and Crook 1976; Wing, Cooper and Sartorius 1974); six are miscellaneous classifications (Berner, Gabriel, Katschnig et al.1983; Kielholz 1972; Klein 1973, 1974; Pollitt 1965; Taylor 1986; Winokur 1974, 1979); and one is a composite diagnostic classification, based on the different classifications included in CODE-DD.

          One would expect low inter-rater agreement in such a complex system like CODE-DD. However, in the first reliability study that included 239 patients there was an 87.8% inter-rater agreement on the presence or absence of the 90-items of the vocabulary (Morey 1991). In the second, inter-rater agreement increased to 100% (Ban, Fjetland, Kutscher and Morey 1993). In a validation study that included 230 of patients with a clinical diagnosis of major depression, there was a 99.6% correspondence between the clinical DSM-III-R and CODE-DD diagnosis of major depression. In another validation study, which included 322 patients, the correspondence was 97.2% (Ban, Fjetland, Kutscher and Morey 1993). CODE-DD was translated and adopted from the English original (Ban 1987) into Estonian (Mehilanen 1992); French (Ferrero, Crocq and Dreyfus 1992); Italian (Aguglia and Forti 1989); Polish (Pużyński S, Jarema M, Wdowiak 1989); and Portuguese (Nardi and Versiani 1990). It was used in a series of clinical studies in the early development of reboxetine, a selective NE re-uptake blocker (Ban, Gaszner, Aguglia et al.1998).

          Findings with CODE-DD correspond with the commonly held view that the DSM-III-R diagnosis of major depression is a broad diagnostic category. If depressive illness were characterized by unmotivated depressed mood, depressive evaluations and lack of reactive mood changes, from the 322 patients with the clinical diagnosis of major depression -- included in the second validation study -- only 119 patients, i.e., 37%, would have qualified for depression. Findings with CODE-DD are also in keeping with the notion that depression consists of more than one form of illness. From the 322 patients only 95 patents, i.e., 29.5%, fulfilled definite criteria of Kraepelin’s depressive states, characterized by motor retardation, retardation of thought and difficulties of concentration; even less, 45 patients, i.e., 14%, fulfilled criteria of Schneider’s vital depression (Kraepelin 1896; Schneider, 1920). The overlap between the two forms of depressive illness was negligible (Ban 2001b).




          To extend the scope of CODE-DD for uncovering depressive diagnoses, the instrument was revised. In the revised instrument (CODE-DD-R, also referred to as CODE-UD), the vocabulary was increased from 90 to 220 variables and the number of diagnostic algorithms from 25 to 84. CODE-UD includes all major diagnostic concepts and classifications of melancholia/depression from Hippocrates (460-377 BC) to the DSM-IVTM (American Psychiatric Association 1994).

          The term “melancholia” was first used in the 5th century BC in reference to all chronic mental syndromes that did not qualify for epilepsy, hysteria or Scythian disease (transvestism) in the Works of Hippocrates (Adams1929). Until the late 18th century the concept of melancholia had virtually no relationship with our current concept of depression. Boissier de Sauvages classified the melancholias as disorders of intellect and William Cullen as disorders of judgment (Cullen 1772; Sauvages 1769).

          Development of our current conceptual framework relevant to depressive illness began in the early 19th century with Johann Christian Heinroth’s recognition that melancholia is a disorder of affect. Heinroth perceived insanity as exaltation or depression of one of three faculties (emotion, intellect, volition) of the mind and classified melancholia as partial insanity characterized by depression of emotions (Heinroth 1818). Twenty years later, by separating lypemania (lupos = sadness) or melancholy of the ancient from the monomanias (intellectual, affective and instinctive), Jean-Etienne Dominique Esquirol, set the stage for a development that led to our current diagnostic concepts and classifications of depression (and also of other mental disorders) (Esquirol 1838; Healy 1997).




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Ban TA, Fjetland OK, Kutscher M, Morey LC. 1993. CODE-DD development of a diagnostic scale for depressive disorders. In: Hindmarch I, Stonier PD, editors. Human Psychopharmacology. Measures and Methods. Vol. 4. Chichester: John Wiley& Sons; 1993, pp. 73-85.

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*Based on Thomas A. Ban: Towards a clinical methodology for neuropsychopharmacology research, published in Neuropsychopharmacologia Hungarica (2007; 9: 81–90).


July 18, 2019